A “Lysosomal Storage Disorder” or “LSD” is a disorder in which lysosomal function has been disrupted due to lysosomal enzymatic failure. There are approximately fifty LSDs, and all are rare inherited diseases in which genes for lysosomal proteins have been mutated. Individually, the frequency of each is less than 1:100,000, but collectively, the frequency is about 1:5,000-1:10,000. The defective enzyme can result in the accumulation of lipids, glycoproteins and mucopolysaccharides in the lysosome. LSDs include, without limitation, Niemann Pick Type C (NPC), Wolman, Niemann Pick Type A, Farber, Tay-Sachs, mucopolysaccharide IIIB (MSIIIB) and tripeptidyl-peptidase I (CLN2 or Batten) diseases.
LSDs are often fatal within a few months or years of birth. The symptoms include developmental delay, movement disorders, abnormal bone growth, pulmonary and cardiac problems, heptomegaly, splenomegaly, dementia, seizures, blindness and/or deafness.
Intracellular vesicular traffic is integral to the operation of lysosomes and endosomes. The accumulation of undegraded substrates impacts the lysosome and endosome function. Lysosomes are involved in a number of cellular processes: phagocytosis, exocytosis, autophagy, immunity, receptor recycling, neurotransmission, signaling intracellularly, bone biology and pigmentation. Disruption in any one of these processes can have severe and usually fatal consequences (Parkinson-Lawrence, E. et al. (2010) Physiology 25:102).
A review of the LSDs and their associated clinical phenotypes has yielded generalizations regarding those phenotypes: 1) each disorder manifests a range of symptoms, which depend on the impact of the genetic mutation; 2) across disorders, there can be phenotypic similarities depending on the affected tissues and the similarity of the accumulated substrates; and 3) there can also be symptoms that distinguish the various disorders (Parkinson-Lawrence et al., supra).
There is no cure for LSDs. However, there is some therapy that has thus far demonstrated limited results in abatement of symptoms. Specifically, enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation may be useful in slowing progression in certain types of LSDs (van Gelder, C M et al. (2012) Expert Opin. Pharmacother. 13(16):2281-99). Additionally, substrate reduction therapy and small molecule chaperones have been also proposed for the treatment of some LSDs.
The traditional accepted function of tocopherols is lipid antioxidants. Due to their physical characteristics and lipid solubility, tocopherols are mostly localized in membranes acting as radical quenchers, according, for example, the oxidation of unsaturated phospholipids. The maintenance of membrane lipid composition and homeostasis is essential for proper function, transport, and protein docking. In the food industry, tocopherols are used to avoid oils becoming rancid.
Ubiquinone or Q10 is a fat-soluble, electron-transporting co-enzyme found in the electron-transport chain in mitochondria. Ubiquinone is a quinone which cyclically can change from an oxidized to a reduced form. Tocopheryl quinones act as poor mitochondrial decouplers, because they compete with Ubiquinone, inhibiting the transference of electrons between complex III and complex I and complex II. Alpha tocopheryl quinone has been used in human clinical trials for the treatment of Friedreich's ataxia, a mitochondrial disorder, with positive results of approving neurological function.
Bascuñan-Castillo et al. “Tamoxifen and vitamin E treatments delay symptoms in the mouse model of Niemann-Pick C,” J. Appl. Genet. 45(4):461-7(2004), describe the improvement in lifespan and motor skills in NPC1 mice upon administration of α-tocopherol. Narashima et al. “Niemann-Pick C1-like 1 mediates alpha-tocopherol transport” Mol. Pharmacol. 74(1):42-9 (2008), describe studies demonstrating that α-tocopherol is absorbed in the intestine via the Niemann-Pick C1-like 1 (NPC1L1) transporter.
Koyama et al. “Synthesis of fluorine analogs of vitamin E. IV. Synthesis of bis(trifluoromethyl)tocopherols” Chem. Pharm. Bull 43(9):1466 (1995), describe synthesis of tocopherol analogues with a halogenated side chain or chromanol ring. Koyama et al. (1995) were studying the spin relaxation times (T2) on fluorine NMR as an indication of how and where the analogues were incorporated into liposomes. Likewise, Koyama et al. “Synthesis of fluorine analogs of vitamin E. IIII. Synthesis of 2-[4,8-dimethyl-12-(trifluoromethyl)tridecyl]-2,5,7,8-tetramethyl-6-chromanol and 2-[4,12-dimethyl-8-(trifluoromethyl)tridecyl]-2,5,7,8-tetramethyl-6-chromanol” Chem. Pharm. Bull 42(10):2154 (1994), describe a tocopherol analogue with a halogenated side chain.
Takiguchi et al., U.S. Pat. No. 6,491,847, describe a quinone derivative having a benzoquinone core and R groups containing a halogenated side chain. These compounds were found to be useful as liquid crystal compounds because of their stable and broad discotic liquid crystal phase.
Gille et al. “Tocopheryl quinones and mitochondrial,” Mol. Nutr. Food Res. 54:601(2010), present evidence that tocopherol and α-tocopheryl quinone can alter mitochondrial respiration by inhibiting Complex III. Müllebner et al. “Modulation of the mitochondrial cytochrome bc1 complex activity by chromanols and related compounds,” Chem. Res. Toxicol. 23(1):193-202 (2010), also demonstrate that tocopheryl quinones can inhibit mitochondrial electron transfer. Yu et. al. “Altered cholesterol metabolism in Niemann-Pick Type C1 mouse brains affects mitochondrial function,” J. Biol. Chem. 280(12):11731-39 (2005), teach that when the mitochondrial membrane potential is decreased, ATP synthesis is decreased.
There has also been research in relation to the treatment of LSDs with cyclodextrins. Rosenbaum et al., “Endocytosis of β-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells,” PNAS Early Edition www.pnas.org/cgi/doi/10.1073/pnas.0914309107 (2010), describe studies that demonstrate that treatment of NPC cells with cyclodextrin results in enhanced exocytic transport of cholesterol to reduce cholesterol accumulation in those mutant cells. Davidson et al. “Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression,” PLoS ONE 4(9):e6951 (2009), describe chronic treatment of NPC mutant mice with cyclodextrin delayed clinical disease onset, delayed neurodegeneration, and increased lifespan.
Thus, there are studies that report that α-tocopherol, related compounds or cyclodextrin can improve LSD symptoms. Nonetheless, there continues to be a clear and urgent need for the development of further pharmaceutical agents for the treatment of LSDs.